Corneal nerve dysfunction is the pathophysiologic basis of many ocular surface diseases, causing considerable morbidity, including neurotrophic keratitis and dry eye disease and therefore corneal nerve health is a prerequisite for the maintenance of vision. Despite the traditional point of view that immune cells are deleterious for nerve regeneration, recent evidence suggests that immune cells can show beneficial effects in neuronal regeneration. For instance, macrophages and conventional dendritic cells are among the key players in providing a neuro-protective and neuro-trophic microenvironment for nerve regeneration following nerve damage. Despite recent evidence on neuro-protective and neuro-regenerative functions of immune cells, the role and source of endogenous neurotrophic molecules in the cornea remains elusive. Moreover, the impact of recently identified plasmacytoid dendritic cells (pDCs), a vital subset of immune cells that reside in the anterior stroma just beneath sub-basal corneal nerve plexus of cornea, remains to be determined. These cells orchestrate and link innate and adaptive immune responses and are implicated in the induction of tolerance to transplanted tissues or tumors. Our preliminary results suggest that pDCs are vital in the maintenance and function of corneal nerves, as we demonstrate that local depletion of pDCs in the cornea leads to abrupt and severe nerve loss and diminishment of corneal sensation. Our hypothesis is that pDCs contribute to maintenance, function, and regeneration of nerves through secretion of neurotrophic molecules. Our specific aims include evaluating the significance of pDCs on corneal nerve maintenance and health as well as studying the impact of pDCs on neural regeneration in the cornea following nerve damage. Our fresh perspective on how pDCs contribute to regulation of corneal nerve microenvironment holds promise of amplifying our knowledge far beyond the current state on the cross talk between nerve fibers and immune cells in the cornea and the impact of such cross talk on corneal nerve health and function. Furthermore, this application suggests in vivo approaches for assessing significance of corneal pDCs, in nerve protection and regeneration. Therefore, this proposal will elucidate the neuro-protective and neuro-regenerative properties of pDCs, may result in novel therapeutic approaches, and is potentially applicable in tissues other than cornea and conditions in which neuro-regeneration is vital, including traumatic nervous system injuries, neurodegenerative diseases, and peripheral neuropathies.